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ORIGINAL ARTICLE

Chest Computed Tomography Is More Likely toShow Latent Tuberculosis Foci Than Simple ChestRadiography in Liver Transplant CandidatesJiwon Lyu,1 Sung-Gyu Lee,2 Shin Hwang,2 Sang-Oh Lee,3 Oh-Hyun Cho,3 Eun Jin Chae,4

Sang Do Lee,1 Woo Sung Kim,1 Dong Soon Kim,1 and Tae Sun Shim11Division of Pulmonary and Critical Care Medicine, 2Division of Hepatopancreatobiliary Surgery and Liver

Transplantation, Department of Surgery, 3Department of Infectious Diseases, and 4Department of

Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical

Center, Songpa-Gu, Seoul, South Korea

Although the detection and treatment of latent tuberculosis infections (LTBIs) in transplant candidates are essential, current

diagnostic methods for LTBIs are limited, especially in immunocompromised subjects. Pretransplant chest computed tomog-

raphy (CT) may reveal more LTBI foci and thus predict the development of posttransplant tuberculosis (TB) more efficiently;

however, this hypothesis has not yet been investigated. Thirty-six liver transplantation (LT) recipients who developed TB

(the TB group) and 144 LT recipients who did not develop TB (the control group) were retrospectively enrolled into a study

with a nested case-control design, and their clinical characteristics and radiological findings were compared. Tuberculin skin

tests (TSTs) were not performed, and none of these patients had been treated for LTBIs. Thirty-six of 2549 LT recipients

(1.4%) were diagnosed with TB after LT (median 10 months, range 1-80 months). Twenty-eight patients (77.8%) suc-

cessfully completed the treatment. There were no significant differences in the clinical characteristics of the 2 groups.

Abnormal CT findings (40.0% versus 17.3%, P 0.018) and chest X-ray (CXR) findings (25.0% versus 11.8%, P 0.044)

suggestive of healed TB were significantly more frequent in the TB group versus the control group. Of the 10 patients who

underwent chest CT and developed TB, 5 (50%) showed abnormal findings only on chest CT scans, whereas their CXR

results were normal. In conclusion, a pretransplant chest CT scan is more likely to show an LTBI than a CXR in those with

post-LT TB. The usefulness of chest CT along with traditional methods such as TSTs for LTBI screening should be furtherinvestigated.Liver Transpl 17:963-968, 2011. VC 2011 AASLD.

Received January 7, 2011; accepted April 11, 2011.

The incidence of tuberculosis (TB) has been estimatedto be 20 to 74 times higher in transplant recipientsversus the general population; moreover, TB in trans-plant recipients is associated with mortality rates ashigh as 30%.1,2 TB in transplant recipients is usuallycaused by the reactivation of a latent tuberculosisinfection (LTBI) rather than the acquisition of a newTB infection.1,3 Therefore, the diagnosis and treat-

ment of LTBIs are generally recommended for trans-plant candidates.4,5 The prevalence of TB infections is

especially high in liver transplantation (LT) recipients;rates of 1% to 6% have been reported in some case se-ries, and they may be even higher in areas endemicfor TB.1,2,6,7 Furthermore, the mortality rates of LTrecipients with LTBIs have been reported to be ashigh as 30% to 100%.1,8,9

Despite the high risk of active TB in LT recipients,there is no consensus regarding the appropriate diag-

nostic and treatment methods for LTBIs.10

Althoughtuberculin skin tests (TSTs) are generally used to

Abbreviations: CNI, calcineurin inhibitor; CT, computed tomography; CXR, chest X-ray; IGRA, interferon-c release assay; LT, livertransplantation; LTBI, latent tuberculosis infection; TB, tuberculosis; TST, tuberculin skin test.

Address reprint requests to Tae Sun Shim, M.D., Division of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine,Asan Medical Center, 388-1 Poongnap-Dong, Songpa-Gu, Seoul, South Korea 138-736. Telephone: 82-2-3010-3892; FAX: 82-2-3010-6968;E-mail: shimts@amc.seoul.kr

DOI 10.1002/lt.22319View this article online at wileyonlinelibrary.com.LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

LIVER TRANSPLANTATION 17:963-968, 2011

VC 2011 American Association for the Study of Liver Diseases.

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screen for TB infections, they do not always diagnoseLTBIs in LT patients. Moreover, according to a previ-ous report,11 the highest risk factor for active post-transplant TB is radiological evidence of a previousTB infection, not positive TST results. Because LTrecipients with radiological features of healed TB are

at high risk for active posttransplant TB, they shouldbe treated for LTBIs regardless of their TST results.1

No studies to date have assessed the usefulness ofchest computed tomography (CT) in screening LT can-didates for LTBIs. Therefore, we retrospectively ana-lyzed the ability of pre-LT chest CT scans to predictthe development of post-LT TB.

PATIENTS AND METHODS

Patients

Patients who underwent primary LT between January1999 and December 2009 at the Asan Medical Centerand survived more than 1 month were retrospectively

evaluated until August 2010. One hundred five of the2654 LT recipients died within 30 days; thus, 2549patients were eligible for this study. Thirty-six of thesepatients developed TB. Using a nested case-controldesign, we selected 4 control subjects who did notdevelop TB and matched those patients who devel-oped TB with respect to sex and age. The comparedfactors included demographic features, comorbidities,a previous history of TB, simple chest X-ray (CXR)and CT findings, the date of LT, the occurrence ofallograft rejection, coinfections with cytomegalovirus,a TB diagnosis, the time from LT to the TB diagnosis,the date of the last follow-up visit, and the date ofdeath. This study was approved by the institutional

review board of the Asan Medical Center.

Immunosuppressive Therapy Protocol

The peritransplant primary immunosuppression proto-cols used for adult LT recipients at our institution con-sisted of an interleukin-2 receptor inhibitor (basilixi-mab) on days 0 and 4, an intraoperative steroid bolus(5-10 mg/kg), an intravenous or oral calcineurin inhibi-tor (CNI), and corticosteroid recycling (which was begunon day 1); adjunctive mycophenolate mofetil was givento patients who showed CNI-associated side effectsand to patients whose immunosuppressive treatmentneeded to be augmented. The oral CNI was usually

tacrolimus. Patients were tapered off the steroid rapidly.Patients showing an intractable intolerance of CNIswere given mycophenolate mofetil monotherapy.

Definition of the TB Diagnosis

TB was diagnosed when (1) Mycobacterium tuberculo-sis or acid-fast bacilli were detected in any clinicalspecimen, (2) any clinical specimen showed a positivepolymerase chain reaction result for M. tuberculosis,(3) a caseating granuloma was found in the tissue, or(4) the clinical findings were compatible with TB andimproved after an anti-TB treatment.

Chest Radiography and CT Scanning

Pre-LT standard posteroanterior and lateral CXRs andCT results, if they were available, were reanalyzed forabnormal lesions suggestive of healed TB and for nor-mal or nonspecific abnormal findings. All CXRs andCT results were analyzed by a radiologist (E.J.C.) and

a pulmonologist (J.L.) blinded to each patients clini-cal history. CXRs were evaluated for fibrotic linearopacities and calcified nodules, and CT findings wereevaluated for fibrotic irregular lines, uncalcified nod-ules, calcified nodules, and fibrotic consolidation. Forpatients with TB, chest CT findings at the time ofdiagnosis were compared with baseline CT findings.After they reviewed the CT findings, the 2 observersreached a final diagnosis by consensus.

Assessment of the Treatment Outcomes

The treatment outcomes (cure, treatment completion,failure, default, and death) were based on the guide-

lines of the World Health Organization.12 Treatmentsuccess was defined as the achievement of both acure and treatment completion.

Statistical Analysis

Results are presented as means and standard devia-tions. Differences between categorical variables wereassessed with the chi-square test or Fishers exacttest (as appropriate), and differences between contin-uous variables were evaluated with unpaired t tests. APvalue

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were diagnosed at 7 months to 1 year, and 5 (13.9%)were diagnosed after 1 year. Twenty-three of these 36patients (63.9%) were diagnosed with pulmonary TB,and 13 (36.1%) were diagnosed with extrapulmonaryTB.

All LT recipients received an anti-TB treatment for amean duration of 10 months with less hepatotoxicdrugs; 34 patients (94.4%) were treated with etham-butol, and 27 (75.0%) were treated with fluoroquino-lone. Thirty patients (83.3%) received isoniazid, and14 (38.9%) received rifampin. Rifabutin was used in11 patients (30.6%) in order to reduce the drug inter-actions with CNIs. Patients showing evidence of hepa-

totoxicity were switched to nonhepatotoxic agents.The treatment success rate was 77.8%. Two patients(5.6%) died, with 1 death (2.8%) related to active TB.The clinical characteristics and outcomes of the LTrecipients with TB are shown in Table 2.

Chest Radiography and CT Scans

All subjects in both groups underwent chest radiogra-phy, whereas only 25 TB subjects (69.4%) and 81 con-trol subjects (56.3%) underwent chest CT scans. Themost common reason for the latter was a metastaticworkup for underlying hepatocellular carcinoma.

Abnormal CXRs suggestive of healed TB wereobserved in 9 TB subjects (25.0%) and 17 control sub-jects (11.8%, P 0.044). In addition, CT scansshowed that abnormal lesions suggestive of healed TBwere more frequent in the TB group versus the controlgroup (40.0% versus 17.3%, P 0.018; Table 1). CXRand chest CT findings did not differ significantlybetween the 2 groups except for fibrotic consolidationon chest CT scans (P 0.011; Table 3). Seven of the10 patients (70%) who underwent chest CT and devel-oped TB after LT showed TB reactivation at the site ofthe healed TB. Moreover, 5 of these 10 patients (50%)showed abnormal findings suggestive of healed TB on

TABLE 1. Baseline Characteristics of the LT Recipients

Characteristic TB Group (n 36) Control Group (n 144) PValue

Age (years)* 51.1 6 9.9 50.6 6 9.6 0.981

Male 26 (72.2) 104 (72.2) 1.000

Indication for LTHepatocellular carcinoma 19 (52.8) 57 (39.6) 0.152

Hepatitis B 15 (41.7) 65 (45.1) 0.708

Other 2 (5.6) 22 (15.3) 0.172Potential risk factors for TB

Diabetes 7 (19.4) 24 (16.7) 0.693

Previous TB history 6 (16.7) 13 (9.0) 0.182

CXR suggestive of healed TB 9 (25.0) 17 (11.8) 0.044CT suggestive of healed TB 10/25 (40.0) 14/81 (17.3) 0.018

Allograft rejection 6 (16.7) 23 (16.0) 0.919

Cytomegalovirus coinfection 1 (2.8) 2 (1.4) 0.490Induction immunosuppression 22 (61.1) 109 (75.7) 0.079

NOTE: The data are presented as numbers and percentages unless otherwise noted.

*The data are presented as means and standard deviations.

TABLE 2. Characteristics of the 36 Patients Who

Developed TB After LT

Characteristic Patients [n (%)]

Location of TB

Pulmonary 23 (63.9)

Extrapulmonary 13 (36.1)Miliary 8 (22.2)

TB pleurisy 3 (8.3)

TB lymphadenopathy 1 (2.8)

TB meningitis 1 (2.8)Diagnostic methods for TB

Acid-fast bacillus smear or

culture (positive)

27 (75.0)

Polymerase chain reaction

forM. tuberculosis(positive)

1 (2.8)

Histology 3 (8.3)Clinical* 5 (13.9)

Drug susceptibility results 22/27 (81.5)

Pansusceptible 19/22 (86.4)

Resistance to isoniazidor streptomycin

3/22 (13.6)

TB treatment regimen

Intensive phase3 drugs 12 (33.3)

4 or more drugs 24 (66.7)

Continuation phase2 drugs 3 (8.3)

3 drugs 14 (38.9)4 drugs 19 (52.8)

Treatment outcomes

Treatment success 28 (77.8)

Death 2 (5.6)

Current treatment 3 (8.3)Transfer 3 (8.3)

*Three of the five patients had TB pleurisy with

lymphocyte-dominant exudates and high adenosine

deaminase concentrations.One death was related to TB, and 1 death was related to

hepatocellular carcinoma.

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chest CT scans, but they had normal chest radiogra-phy results (Table 4 and Fig. 1).

DISCUSSION

To the best of our knowledge, no previous reports haveassessed the effectiveness of pretransplant chest CT inpredicting the development of TB after LT; thus, thisstudy is the first to show that chest CT findings sugges-tive of healed TB can predict the development of TB inLT recipients. The number of patients enrolled in ourstudy was large in comparison with previous studies,and LTBI screening or treatment was not performedbefore LT; this allowed an assessment of the natural

course of TB after LT. Furthermore, most of thepatients developed TB within 1 year of transplantationat the site of the healed TB. These findings suggest thatmost post-LT patients develop TB through the reactiva-tion of old foci and not through new infections.

Because TSTs remain the standard method fordetecting LTBIs, isoniazid is recommended for TST-positive organ transplant recipients.1,4,5 TSTs, how-ever, cannot detect LTBIs in many LT recipients, andradiological features of a previous TB infection are astronger risk factor for active posttransplant TB thanpositive TST results.11 Because TSTs have low sensitiv-ity in immunocompromised patients and low specificity

due to a previous bacillus Calmette-Guerin vaccinationor an infection with nontuberculous mycobacteria,TSTs have several limitations in transplant recipients,especially in countries with an intermediate to high TBburden.13 Korea has an intermediate TB burden; thus,a treatment based on TST results in Korean LT recipi-ents has not been determined. In addition, LT recipi-ents are potentially at risk for hepatotoxicity associatedwith anti-TB treatments. Most transplant centers inKorea, including ours, neither test for LTBIs nor treatthem in LT candidates.

The need for more accurate tests for detecting LTBIsin LT candidates has led to the use of interferon-crelease assays (IGRAs). The QuantiFERON-TB Gold

assay (Cellestis, Ltd., Carnegie, Australia) has beenfound to be comparable to TSTs in the diagnosis ofLTBIs,14 whereas the T-SPOT.TB assay (OxfordImmunotec, Abingdon, United Kingdom) has beenfound to be more useful for diagnosing LTBIs in thesepatients.15 Further studies of the best diagnosticmethods for detecting LTBIs, including combinationsof individual methods such as TSTs, IGRAs, and chestCT scans, are needed.

Many reports have described the usefulness of CTin finding additional cases of TB disease missed onCXRs under heterogeneous clinical conditions.16-18

Even theoretically, chest CT is better than a simple

TABLE 3. Pretransplant CXR and CT Findings in LT Recipients

Characteristic TB Group (n 36) Control Group (n 144) PValue

CXR suggestive of healed TB 9 (25.0) 17 (11.8) 0.044

Fibrotic linear opacities 7 (19.4) 15 (10.4) 0.157

Calcified nodules 7 (19.4) 12 (8.3) 0.068CT suggestive of healed TB 10/25 (40.0) 14/81 (17.3) 0.018

Irregular lines 6 (24.0) 11 (13.6) 0.224

Uncalcified nodules 3 (12.0) 4 (4.9) 0.352Calcified nodules 8 (32.0) 11 (13.6) 0.069

Fibrotic consolidation 4 (16.0) 1 (1.2) 0.011

NOTE: The data are presented as numbers and percentages.

TABLE 4. Sites of TB in 10 Patients With Healed TB Lesions on Chest CT Images

Patient

Pre-LT Presence of

Healed TB Sites of TB on Chest CT Images

CXR Chest CT Pre-LT Post-LT Same Site

1 Yes Yes Right upper lobe Right upper lobe Yes

2 No Yes Left upper lobe Left upper lobe Yes3 Yes Yes Both upper lobes Right upper lobe Yes

4 No Yes Right upper lobe Right upper lobe Yes

5 Yes Yes Left upper lobe Miliary TB No6 Yes Yes Right upper lobe Right upper lobe Yes

7 No Yes Right upper lobe Right upper lobe Yes

8 Yes Yes Both upper lobes Left upper lobe Yes9 No Yes Right lower lobe Right upper lobe No

10 No Yes Right upper lobe Miliary TB No

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CXR for detecting calcified mediastinal and hilar

lymph nodes. In our previous study,16

chest CT scansalong with TSTs and IGRAs were effective in differenti-ating between subjects with active TB infections, sub-jects with LTBIs, and uninfected subjects in a contactinvestigation. Lee et al.17 described the usefulness ofhigh-resolution CT scanning, which may be helpful indifferentiating active TB from LTBIs in outbreak inves-tigations of TB. Nakanishi et al.18 reported that high-resolution CT findings such as a tree-in-bud appear-ance, lobular consolidation, and large nodules weresignificantly associated with an increased risk for pul-monary TB. In this study, abnormal lesions sugges-tive of healed TB appeared more frequently in chestCT scans for the TB group versus the control group

(40.0% versus 17.3%, respectively, P 0.018). How-ever, we should also recognize the limitations of CTscanning in the diagnosis or prediction of TB. Mala-viya et al.19 reported that a chest CT scan was neverpositive unless a TST or an IGRA was positive inpatients with inflammatory rheumatic disease whowere treated with a tumor necrosis factor a inhibitor.In our study, the proportions of pre-LT abnormalitiessuggestive of healed TB did not significantly differbetween the CT (40.0%) and CXR images (25.0%) forthe TB group, and 15 patients (60%) who developedTB after transplantation had normal pre-LT chest CTfindings. Collectively, these findings suggest that eventhough chest CT has the potential to play a role as a

predictor of the future development of TB after LT andis possibly better than CXRs in this respect, chest CTalone has limited value as a predictor of the develop-ment of TB in LT recipients. Further studies that com-bine, for example, TSTs, IGRAs, and CXRs or CT areneeded.

Traditionally, the development of TB in immuno-suppressed patients occurs via the reactivation oflatent foci and not via new infections, especially inareas with a low incidence of TB. Several recent stud-ies, however, have suggested that TB recurs mostlyvia new infections rather than reactivation, especiallyin areas with a high incidence of TB.20,21 Although

our study was performed in a country with an inter-

mediate TB burden, our results suggest that most ofthe patients developed TB via the reactivation of latentfoci and not through new infections. That is, most ofthe patients who developed TB did so within 1 yearafter LT, with 70% developing TB at the site of thehealed TB lesions.

This study has several limitations, including thoseinherent to all retrospective studies at a single center.In addition, not all patients underwent chest CT, andthe medical records lacked information about thebacillus Calmette-Guerin vaccination status anddetailed histories of previous TB infections and con-tact with TB-infected patients. Moreover, TSTs, thestandard method for detecting LTBIs, were not eval-

uated in this study, primarily because TSTs have ahigh false-positive rate due to the high rates of bacil-lus Calmette-Guerin vaccination and a high false-negative rate due to immunosuppression.

In conclusion, our findings show that among thosewith post-LT TB, a pretransplant chest CT scan ismore likely to show an LTBI than a CXR in a TB-endemic country. However, the usefulness of chest CTin predicting the development of TB after LT shouldbe further investigated, especially in combination withthe current standard method (TSTs) and/or newmethods (IGRAs) for detecting LTBIs.

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Figure 1. Representative chestradiography and CT images. (A) Apretransplant CXR appeared to benormal, but (B) pretransplantchest CT scanning revealed a TB-suggestive lesion (an uncalcifiednodule). (C) Active TB developed 6months after LT in the samelocation.

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